Human platelets and their capacity of binding viruses: Meaning and challenges?

Blood platelets are first aimed at ensuring primary hemostasis. Beyond this role, they have been acknowledged as having functions in the maintenance of the vascular arborescence and, more recently, as being also innate immune cells, devoted notably to the detection of danger signals, of which infectious ones. Platelets express pathogen recognition receptors that can sense bacterial and viral moieties. Besides, several molecules that bind epithelial or sub-endothelial molecules and, so forth, are involved in hemostasis, happen to be able to ligate viral determinants, making platelets capable of either binding viruses or even to be infected by some of them. Further, as platelets express both Fc-receptors for Ig and complement receptors, they also bind occasionally virus-Ig or virus-Ig-complement immune complexes. Interplays of viruses with platelets are very complex and viral infections often interfere with platelet number and functions. Through a few instances of viral infections, the present review aims at presenting some of the most important interactions from pathophysiological and clinical points of view, which are observed between human viruses and platelets.Fil: Chabert, Adrien. Universite Lyon 2; FranciaFil: Hamzeh Cognasse, Hind. Universite Lyon 2; FranciaFil: Pozzetto, Bruno. Universite Lyon 2; FranciaFil: Cognasse, Fabrice. Universite Lyon 2; FranciaFil: Schattner, Mirta Ana. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; ArgentinaFil: Gomez, Ricardo Martin. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto de Biotecnología y Biología Molecular. Universidad Nacional de La Plata. Facultad de Ciencias Exactas. Instituto de Biotecnología y Biología Molecular; ArgentinaFil: Garraud, Olivier. Universite Lyon 2; Franci

Modelling and simulation of blood collection systems: improvement of human resources allocation for better cost-effectiveness and reduction of candidate donor abandonment

International audienceFormal Petri net models were used to describe all relevant donor flows of the various blood collection systems; the Petri net models were converted onto discrete-event simulation models, allowing the evaluation of a large number of scenarios and configurations of blood collection systems. Quantitative models were proposed that encompassed all components of the blood collection systems, such as the donor arrival process, resource capacities and performance indicators. Appropriate experimental designs and cost-effectiveness analyses were used to determine the best configurations of human resources and donor appointment strategies

Direct contact of platelets and their released products exert different effects on human dendritic cell maturation

<p>Abstract</p> <p>Background</p> <p>Dendritic cells (DCs) are antigen presenting cells capable of inducing innate and adaptive immune responses. According to the stimulus and their maturation state, DCs induce immunogenic or tolerogenic responses. Platelets (PLTs), which are involved in haemostasis and inflammation, can also interact with DCs. In this study, we examined the effect of PLTs on DC maturation <it>in vitro</it>. Human monocyte-derived DCs were co-cultured for 2 days with homologous PLTs either in the same well or in 0.4 μm-pore size filter-separated compartments.</p> <p>Results</p> <p>Confocal microscopy showed the attachment of PLTs to DC membranes. The DC receptor involved in this interactions was found to be CD162. In addition, we observed that DCs co-cultured with PLTs in filter-separated compartments acquired a mature phenotype (high CD80, CD86, and intermediate CD83 expression; IL-12(p70) production; efficient stimulation of autologous CD4+ T cell proliferation), while DCs co-cultured with PLTs in the same compartment did not undergo phenotypic maturation, did not secrete IL-12(p70) or IL-1β, but instead induced moderate Th2-polarized T cell proliferation.</p> <p>Conclusion</p> <p>These data indicate that (i) PLTs secrete a soluble DC-activating factor that was demonstrated not to be soluble CD40-Ligand (CD154; as could have been expected from <it>in vivo </it>and previous <it>in vitro </it>work) but to be nucleotide, and (ii) that cell-to-cell contact did not induce DC maturation, possibly because nucleotide release by PLTs was prevented by direct contact with DCs. This work demonstrates that PLTs are active elements of the immune system that might play a role in balancing the ability of DCs to polarize T cell responses, therefore making them critical factors in transfusion processes.</p

Rôle inflammatoire des plaquettes sanguines (application en transfusion)

Les plaquettes sanguines sont des cellules qui ont un rôle majeur au cours des processus de l hémostase primaire et jouent un rôle primordial dans l immunité innée mais aussi adaptative. Ces cellules anucléées ont une capacité sécrétoire très importante de facteurs solubles notamment de cytokines, de chimiokines (CK/CH) et de facteurs immunomodulateurs. L émergence du rôle inflammatoire des plaquettes sanguines dans la communauté scientifique a soulevé de nombreuses questions auxquelles nous essayons de répondre dans ce manuscrit. La majorité de ces questions repose sur la capacité de ces cellules anucléées à répondre de manière régulée à des stimuli complexes. Nos investigations pour répondre à ces questions ont été réalisées dans un contexte transfusion sanguine. Au cours de nos travaux, nous avons mis en évidence la corrélation des profils de sécrétion plaquettaire avec les récepteurs membranaires et les voies de signalisations intraplaquettaires engagées. Les plaquettes expriment plusieurs récepteurs immunitaires sur leur surface notamment les Pattern recognition receptors (PRR) et des récepteurs aux CK/CH. Nous avons démontré et caractérisé la fonction d un nouveau récepteur plaquettaire, le Siglec-7. Ce récepteur est localisé dans les granules a ; son expression sur la membrane est corrélée avec l état d activation plaquettaire. Le Siglec-7 a une avidité élevée avec les molécules composées d a2,8-disialyl (NeuAca2,8NeuAca2,3Gal) et de a2,6-sialyl (Gal-b1,3[NeuAca2,6]HexNAc) (comme les gangliosides GD2, GD3 et GT1b). L engagement de ce récepteur peut induire l apoptose plaquettaire par la voie intrinsèque et extramitochondriale. Ce processus nécessite l engagement du récepteur GPIIbIIIa et P2Y1 et la signalisation de la voie de PI3k. Nous avons également étudié et mis en évidence une composante inflammatoire multifactorielle dans les effets indésirables des receveurs (EIR) et trouvé dans les concentrés plaquettaires (CP), plusieurs facteurs solubles ayant une valeur prédictive élevée pour la survenue des EIR, notamment le sCD40L et l IL-13. Nous avons confirmé que la concentration de ces facteurs augmente au cours de temps de stockage des CP, étant, en partie, responsable du taux élevé de l EIR des CP âgés. Enfin, en plus de la conservation, les processus de préparation des CP peuvent aussi avoir des impacts sur les propriétés inflammatoires des plaquettes. Ces travaux montrent que la réponse inflammatoire plaquettaire est régulée en fonction du stimulus, permettant d argumenter sur le rôle présumé de sentinelle des plaquettes sanguines humaines. Ainsi, mes travaux s inscrivent dans la ré-exploration de la fonction inflammatoire des plaquettes sanguines et l étude du rôle des plaquettes comme cellules de l immunité à composante inflammatoireBlood platelets are non-nucleated cells and play a major role in primary hemostasis and a key role in inflammation, innate and adaptive immunity. They secrete a large variety of soluble factors including cytokines/chemokines (CK/CH) and immunomodulator factors. The emergence of their inflammatory role has raised numerous questions based on the ability of platelets to respond to complex stimuli. Our investigations to answer these questions were realized in the context of platelet component transfusion. In our study, we demonstrated the correlation between the platelet secretion of soluble factors with their membrane receptors and the signaling pathways involved. Platelets express many immune receptors on their surface, including "Pattern recognition receptors" (PRRs) and receptor for CK/CH. We discovered and characterized the function of a new platelet receptor, the Siglec-7. This receptor is located in the granules a and its expression is correlated to the platelet activation level. The Siglec -7 has a high avidity with the molecules composed of a2,8-disialyl (NeuAca2,8NeuAca2,3Gal) and of a2,6-sialyl (Gal-b1,3[NeuAca2,6]HexNAc) (ganglioside GD2 , GD3 and GT1b). Stimulation of this platelet receptor may induce platelet apoptosis by the intrinsic and extramitochondrial pathway. This process requires the engagement of GPIIbIIIa and P2Y1 receptor and the PI3K pathway. We also demonstrated a multifactorial inflammatory component in adverse effects issuing from platelets transfusion, and identified many soluble factors which have a high predictive value of Acute Transfusion Reactions (ATR) occurrence, such as sCD40L and IL- 13. We confirmed that the concentration of these factors increases during storage time of platelet component (PC), being partly responsible for the high rate of ATR by old PC. Finally, in addition to the PC conservation, the process of PC preparation may also have impacts on the inflammatory properties of platelets. These studies showed that the platelet inflammatory response is regulated by the stimulus, explaining the sentinel role of human blood platelets. Therefore, my work contributes to the re-exploration of inflammatory function of these cells and studies their role as an immune cell with an inflammatory componentST ETIENNE-Bib. électronique (422189901) / SudocSudocFranceF

Platelet α-granules modulate the inflammatory response under systemic lipopolysaccharide injection in mice.

BACKGROUND: Beyond their role in hemostasis and thrombosis, platelets are also important mediators of inflammation by the release of hundreds of factors stored in their α-granules. Mutations in Nbeal2 cause gray platelet syndrome (GPS), characterized by the lack of platelet α-granules. This study aims to evaluate the immunological (proinflammatory) effects of platelet α-granules. STUDY DESIGN AND METHODS: We performed an experiment using Nbeal2-/- mice, the mouse model of GPS. Systemic inflammation was induced by intravenous injection of lipopolysaccharide (LPS). Inflammatory response was assessed by quantification of inflammatory soluble factors and platelet biological response modifiers. RESULTS: The lack of Nbeal2 (in Nbeal2 -/- mice, compared with controls) significantly reduced the recruitment of circulating neutrophils and monocytes. Moreover, after LPS injection, there was a significant increase in neutrophil and monocyte counts in control animals, compared with Nbeal2 -/- mice. The control of inflammation, evaluated by the production of anti-inflammatory cytokines, appeared to be greater in Nbeal2-/- mice compared with controls. Conversely, the production of certain inflammatory-soluble mediators known to characterize normal platelet secretion, such as soluble CD40 ligand (sCD40L), was decreased under experimental inflammation in Nbeal2 -/- mice. CONCLUSIONS: These results show that α-granules play a direct role in platelet-mediated inflammation balance, confirming the need to further investigate platelet-associated inflammatory pathophysiology and inflammatory adverse events related to blood transfusion.Supported by grants from the French Blood Establishment (Grant APR), France; the Agence Nationale de la Sécurité et du Médicament et des Produits de Santé (AAP‐2012‐011, Reference 2012S055); the French “Agence Nationale de la Recherche” (ANR‐12‐JSV1‐0012‐01); and the Association “Les Amis de Rémi” Savigneux, France

Specific Antibody Production by Blood B Cells is Retained in Late Stage Drug-naïve HIV-infected Africans

Unseparated peripheral blood mononuclear cells (PBMCs) obtained from drug-naïve African individuals living in a context of multi-infections and presenting with high viral load (VL), were cultured in vitro and tested for their ability to produce antibodies (Abs) reacting with HIV-1 antigens. Within these PBMCs, circulating B cells were differentiated in vitro and produced IgG Abs against not only ENV, but also GAG and POL proteins. Under similar experimental conditions, HAART treated patients produced Abs to ENV proteins only. The in vitro antibody production by drug-naïve individuals' PBMCs depended on exogenous cytokines (IL-2 and IL-10) but neither on the re-stimulation of reactive cells in cultures by purified HIV-1-gp 160 antigen nor on the re-engagement of CD40 surface molecules. Further, it was not abrogated by the addition of various monoclonal Abs (mAbs) to co-stimulatory molecules. This suggests that the in vitro antibody production by drug-naïve individuals' PBMCs resulted from the maturation of already envelope and core antigen-primed, differentiated B cells, presumably pre-plasma cells, which are not known to circulate at homeostasy. As in vitro produced Abs retained the capacity of binding antigen and forming complexes, this study provides pre-clinical support for functional humoral responses despite major HIV- and other tropical pathogen-induced B cell perturbations

Default in plasma and intestinal IgA responses during acute infection by Simian Immunodeficiency Virus.

International audienceABSTRACT: BACKGROUND: Conflicting results regarding changes in mucosal IgA production or in the proportions of IgA plasma cells in the small and large intestines during HIV-infection have been previously reported. Except in individuals repeatedly exposed to HIV-1 but yet remaining uninfected, HIV-specific IgA are frequently absent in mucosal secretions from HIV-infected patients. However, little is known about the organization and functionality of mucosal B-cell follicles in acute HIV/SIV infection during which a T-dependent IgA response should have been initiated. In the present study, we evaluated changes in B-cell and T-cell subsets as well as the extent of apoptosis and class-specific plasma cells in Peyer's Patches, isolated lymphoid follicles, and lamina propria. Plasma levels of IgA, BAFF and APRIL were also determined. RESULTS: Plasma IgA level was reduced by 46 percent by 28 dpi and no IgA plasma cells were found within germinal centers of Peyer's Patches and isolated lymphoid follicles. This lack of a T-dependent IgA response occurs although germinal centers remained functional with no sign of follicular damage, but a prolonged survival of follicular CD4+ T-cells and normal generation of IgG plasma cells is observed. Whereas the average plasma BAFF level was increased by 4.5-fold and total plasma cells were 1.7 to 1.9-fold more numerous in the lamina propria, the relative proportion of IgA plasma cells in this effector site was reduced by 19 percent (duodemun) to 35 percent (Ileum) at 28 dpi. CONCLUSION: Our data provide evidence that SIV is unable to initiate a T-dependent IgA response during the acute phase of infection and favors the production of IgG (ileum) or IgM (duodenum) plasma cells at the expense of IgA plasma cells. Therefore, an early and generalized default in IgA production takes place during the acute of phase of HIV/SIV infection, which might impair not only a virus-specific antibody response but also IgA responses to other pathogens and vaccines as well. Understanding the mechanisms that impair IgA production during acute HIV/SIV infection is crucial to improve virus-specific response in mucosa and control microbial translocation